RNF34 functions in immunity and selective mitophagy by targeting MAVS for autophagic degradation
RNF34 functions in immunity and selective mitophagy by targeting MAVS for autophagic degradation
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RNF34 通过靶向 MAVS 进行自噬降解，在免疫和选择性线粒体自噬中发挥作用
DOI：
10.15252/embj.2018100978
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发表时间：
2019-07-15
期刊：
影响因子：
11.4
通讯作者：
Zhong, Hui
中科院分区：
文献类型：
--
作者：
He, Xiang;Zhu, Yongjie;Zhong, Hui
病毒感染触发线粒体抗病毒信号蛋白(MAV)聚集体的形成，从而有效地促进免疫信号的传递。自噬在控制MAV介导的抗病毒信号中起着重要作用；然而，MAV靶向自噬降解的确切分子机制尚不清楚。在这里，我们研究了RNF34通过靶向MAV来调节免疫和有丝分裂的机制。病毒感染后，RNF34与线粒体内的MAV结合，负向调节RIG-I样受体(RLR)介导的抗病毒免疫。此外，RNF34在Lys 297、311、348和362 Arg上催化K27/K29连接的MAV泛素化，这是依赖NDP52的自噬降解的识别信号。具体地说，RNF34主要在Lys 311处启动MAV上K63-到K27连锁的泛素化转变，这促进了RAG-I刺激下MAV的自噬降解。值得注意的是，在病毒感染时，RNF34是清除受损线粒体所必需的。因此，我们阐明了RNF34介导的MAV自噬降解调节先天免疫反应、线粒体动态平衡和感染的机制。
Viral infection triggers the formation of mitochondrial antiviral signaling protein (MAVS) aggregates, which potently promote immune signaling. Autophagy plays an important role in controlling MAVS-mediated antiviral signaling; however, the exact molecular mechanism underlying the targeted autophagic degradation of MAVS remains unclear. Here, we investigated the mechanism by which RNF34 regulates immunity and mitophagy by targeting MAVS. RNF34 binds to MAVS in the mitochondrial compartment after viral infection and negatively regulates RIG-I-like receptor (RLR)-mediated antiviral immunity. Moreover, RNF34 catalyzes the K27-/K29-linked ubiquitination of MAVS at Lys 297, 311, 348, and 362 Arg, which serves as a recognition signal for NDP52-dependent autophagic degradation. Specifically, RNF34 initiates the K63- to K27-linked ubiquitination transition on MAVS primarily at Lys 311, which facilitates the autophagic degradation of MAVS upon RIG-I stimulation. Notably, RNF34 is required for the clearance of damaged mitochondria upon viral infection. Thus, we elucidated the mechanism by which RNF34-mediated autophagic degradation of MAVS regulates the innate immune response, mitochondrial homeostasis, and infection.